Transient Phenomena in Gene Expression after Induction of Transcription

Deneke, Carlus; Rudorf, Sophia; Valleriani, Angelo

doi:10.1371/journal.pone.0035044

Cited by 10 publications

(15 citation statements)

References 27 publications

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“…We observed the decline in translation efficiency, which was probably attributable to the delay in ribosomal loading on newly exported mRNA, as previously described [23,31,32]. The inflammatory response genes and feedback genes presented seemingly decreased tendency in translation efficiency in LPS and LPS + DEX conditions.…”

Section: Discussionsupporting

confidence: 85%

“…Each seed sequence position is indicated below the miRNA sequences colored in red. acute increases in mRNA levels could lead to a nominal decrease in translation efficiency [23,31,32], the currently observed decrease in translation efficiency could be due to the rapidly enhanced mRNA levels that had just been exported from the nucleus and still had not been loaded by ribosomes.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide Analysis of Acute Inflammatory and Anti-Inflammatory Responses in RAW264 Cells Suggests cis-Elements Associated with Translational Regulation

Sako¹,

Suzuki²

2016

J Data Mining Genomics Proteomics

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Translational regulation plays pivotal roles in mediating inflammatory responses. Glucocorticoids, represented in this study by dexamethasone (DEX), are widely recognized anti-inflammatory agents that exert significant inhibitory effects on the translation of diverse gene groups, including inflammatory genes. However, their regulation is highly complex and diverse, involving transcriptional and translational regulation. Although transcriptional regulation has been investigated by genome-wide transcriptome analyses, translational regulation has been studied by only a few specific gene targets (e.g., Tumor necrosis factor) and the global impact of glucocorticoids on translation levels has scarcely been studied, mainly due to its technical difficulty. Here, using ribosome profiling coupled with high-throughput mRNA sequencing (mRNA-Seq) in which footprints of translating ribosomes can be captured, we conducted a genomewide transcriptional and translational analysis of the acute inflammatory or anti-inflammatory responses of RAW264 cells stimulated by lipopolysaccharide (LPS) or LPS coupled with DEX (LPS + DEX). We showed that the majority of the differential regulation between LPS alone and LPS + DEX were predominated by translation levels rather than transcription levels. Further analysis on the up-and down-regulated gene clusters revealed putative cis regulatory elements exclusively enriched in the 3ʹ-UTR of either up-or down-regulated genes induced by LPS + DEX. The results imply an alternative to the currently recognized mechanisms of glucocorticoid-induced translational regulation in the acute inflammatory response of RAW264 cells. Journal of

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Genome-wide Analysis of Acute Inflammatory and Anti-Inflammatory Responses in RAW264 Cells Suggests cis-Elements Associated with Translational Regulation

Sako¹,

Suzuki²

2016

J Data Mining Genomics Proteomics

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“…For this purpose, we used the ARE Score algorithm, which assigns a numeric value to the putative strength on an ARE [23]. As shown in Figure 5A, mRNAs whose levels increase significantly and therefore belong to group g1 or g3 (Figure 4) have significantly higher ARE Scores than mRNAs in g0 (p<0.001, two-sided Wilcoxon rank sum test).…”

Section: Resultsmentioning

confidence: 99%

Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation

et al. 2014

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For a rapid induction and efficient resolution of the inflammatory response, gene expression in cells of the immune system is tightly regulated at the transcriptional and post-transcriptional level. The control of mRNA translation has emerged as an important determinant of protein levels, yet its role in macrophage activation is not well understood. We systematically analyzed the contribution of translational regulation to the early phase of the macrophage response by polysome fractionation from mouse macrophages stimulated with lipopolysaccharide (LPS). Individual mRNAs whose translation is specifically regulated during macrophage activation were identified by microarray analysis. Stimulation with LPS for 1 h caused translational activation of many feedback inhibitors of the inflammatory response including NF-κB inhibitors (Nfkbid, Nfkbiz, Nr4a1, Ier3), a p38 MAPK antagonist (Dusp1) and post-transcriptional suppressors of cytokine expression (Zfp36 and Zc3h12a). Our analysis showed that their translation is repressed in resting and de-repressed in activated macrophages. Quantification of mRNA levels at a high temporal resolution by RNASeq allowed us to define groups with different expression patterns. Thereby, we were able to distinguish mRNAs whose translation is actively regulated from mRNAs whose polysomal shifts are due to changes in mRNA levels. Active up-regulation of translation was associated with a higher content in AU-rich elements (AREs). For one example, Ier3 mRNA, we show that repression in resting cells as well as de-repression after stimulation depends on the ARE. Bone-marrow derived macrophages from Ier3 knockout mice showed reduced survival upon activation, indicating that IER3 induction protects macrophages from LPS-induced cell death. Taken together, our analysis reveals that translational control during macrophage activation is important for cellular survival as well as the expression of anti-inflammatory feedback inhibitors that promote the resolution of inflammation.

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“…Eq. (11) holds when the creation and degradation of mRNA are in balance and is valid for any functional form of the lifetime distribution [27], [44].…”

Section: Models and Methodsmentioning

confidence: 99%

“…[27], [44]. Let be the total number of mRNAs transcribed with a constant rate and be the number of mRNAs still alive at any time t .…”

Section: Models and Methodsmentioning

confidence: 99%

Complex Degradation Processes Lead to Non-Exponential Decay Patterns and Age-Dependent Decay Rates of Messenger RNA

2013

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Experimental studies on mRNA stability have established several, qualitatively distinct decay patterns for the amount of mRNA within the living cell. Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified. The central aim of this paper is to bring together both the experimental evidence about the decay patterns and the biochemical knowledge about the multi-step nature of mRNA degradation in a coherent mathematical theory. We first introduce a mathematical relationship between the mRNA decay pattern and the lifetime distribution of individual mRNA molecules. This relationship reveals that the mRNA decay patterns at steady state expression level must obey a general convexity condition, which applies to any degradation mechanism. Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation. We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs. Thereby, we show how to extract single-molecule properties of an mRNA, such as the age-dependent decay rate and the residual lifetime. Finally, we analyze the decay patterns of the whole translatome of yeast cells and show that yeast mRNAs can be grouped into three broad classes that exhibit three distinct decay patterns. This paper provides both a method to accurately analyze non-exponential mRNA decay patterns and a tool to validate different models of degradation using decay data.

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Transient Phenomena in Gene Expression after Induction of Transcription

Cited by 10 publications

References 27 publications

Genome-wide Analysis of Acute Inflammatory and Anti-Inflammatory Responses in RAW264 Cells Suggests cis-Elements Associated with Translational Regulation

Genome-wide Analysis of Acute Inflammatory and Anti-Inflammatory Responses in RAW264 Cells Suggests cis-Elements Associated with Translational Regulation

Translational Regulation of Specific mRNAs Controls Feedback Inhibition and Survival during Macrophage Activation

Complex Degradation Processes Lead to Non-Exponential Decay Patterns and Age-Dependent Decay Rates of Messenger RNA

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